Parkinson's Disease, the second most common neurodegenerative disorder, is a complex multifactorial disease with no known disease-modifying therapeutic treatments. DJ-1 is one of the most frequently mutated genes in patients with early-onset familial parkinsonism, and a number of findings from our studies and others indicate that this broadly distributed and highly stable protein may be neuroprotective in response to cellular stresses. We therefore hypothesize that increasing the level of DJ-1 protein in the brain may represent a novel approach for treating PD and potentially other related neurodegenerative diseases. Here we propose to develop and implement a high-throughput rational target-based screen for compounds that increase the expression of DJ-1. In preliminary experiments, we have constructed neural cell lines that stably express a human DJ-1 promoter-directed luciferase reporter protein and have validated this cellular assay by identifying several histone deacetylase (HDAC) inhibitor compounds that transcriptionally activate DJ-1 both in vitro and in vivo. We will build on this promising experimental foundation to identify potential therapeutic leads for PD via the following specific aims: (1) Establish a robust high-throughput screening (HTS) protocol and secondary assay screening tree for identification of inducers of DJ-1 expression. (2) Identify inducers of DJ-1 expression by screening a proprietary library of ~50,000 compounds. (3) Select DJ-1 inducing compounds for preclinical evaluation in Phase II by characterizing their cytotoxic and neuroprotective effects. Our goal is to identify at least one compound that induces DJ-1 expression at micromolar or lower concentrations, shows DJ-1 selectivity (ideally at a ratio of DJ-1/other tested targets >3), is toxic ideally only at concentrations > 5x the effective dose and produces protective effects when tested on primary neurons subjected to experimental degenerative stresses. The subsequent Phase II project will focus on the validation of actives in one or more animal models of PD, chemical optimization as needed and translational studies (chemical scale-up, animal safety and efficacy, ADME/T) required to support the submission of an investigational new drug application. The results from this research will also enable us to validate DJ-1 up- regulation as a pharmacological target for PD and to develop chemical probes to investigate the actions of DJ-1 in cellular and animal systems. Parkinson's disease is the second most common neurodegenerative disease, affecting over 1 million patients in North America alone. Current clinically approved medicines for Parkinson's disease help alleviate disease symptoms, but do not slow the progression of the underlying disease. We propose to identify potential new medicines that will suppress or reverse the underlying Parkinson's disease process, and as a result improve the health and lifespan of people with Parkinson's disease. [unreadable] [unreadable] [unreadable]